Badn Wiaam, Kalliomäki Suzanne, Widegren Bengt, Sjögren Hans Olov
Glioma Immunotherapy Group, The Rausing Laboratory, Division of Neurosurgery, Department of Clinical Sciences, Lund University, Lund, Sweden.
Clin Cancer Res. 2006 Aug 1;12(15):4714-9. doi: 10.1158/1078-0432.CCR-05-2807.
Although there is a need to enhance the therapeutic efficiency in cancer by combining immunotherapeutic procedures with other therapy, combination with chemotherapy is complicated due to immunosuppressive effects of most chemotherapeutic drugs. The purpose of this investigation was to study whether combining tumor cell immunization with the vascular targeting drug combretastatin A4 phosphate (CA4P) would enhance tumor retardation and/or affect the antitumor immune response.
Rats with intrahepatic colon carcinoma were immunized weekly with IL-18/IFNgamma-transfected tumor cells, starting day 9, and were treated with a low-dose CA4P (2 mg/kg, 5 days a week starting day 7). The effect of CA4P was studied on tumor growth and on immune reactivity in vitro.
Rats with preexisting tumor, immunized and treated with low-dose CA4P, had a significantly retarded tumor growth compared with rats receiving CA4P or immunization alone. Splenocytes from rats treated with this combination had a significantly enhanced antitumor immune response compared with splenocytes from control rats. Exposure of nonadherent splenocytes to CA4P in vitro did not enhance their proliferation. However, 3-hour pretreatment of adherent splenocytes with 0.3 microg/mL CA4P significantly enhanced proliferation and IFNgamma production of admixed nonadherent splenocytes, partly due to nitric oxide reduction. Combining the nitric oxide synthase inhibitor N-nitro-l-arginine methyl ester with CA4P and immunization further retarded tumor growth.
Concomitant treatment of rats with progressively growing tumor with immunization and low-dose CA4P significantly enhances the therapeutic effect as compared with either treatment alone and results in an enhanced antitumor immune reactivity.
尽管有必要通过将免疫治疗程序与其他疗法相结合来提高癌症治疗效果，但由于大多数化疗药物的免疫抑制作用，与化疗联合使用会变得复杂。本研究的目的是探讨将肿瘤细胞免疫疗法与血管靶向药物磷酸考布他汀A4（CA4P）联合使用是否会增强肿瘤抑制作用和/或影响抗肿瘤免疫反应。
从第9天开始，每周用白细胞介素-18/γ干扰素转染的肿瘤细胞对肝内结肠癌大鼠进行免疫，并从第7天开始用低剂量CA4P（2mg/kg，每周5天）进行治疗。研究了CA4P对肿瘤生长和体外免疫反应性的影响。
与单独接受CA4P或免疫治疗的大鼠相比，预先存在肿瘤且接受低剂量CA4P免疫治疗的大鼠肿瘤生长明显受到抑制。与对照大鼠的脾细胞相比，接受这种联合治疗的大鼠的脾细胞具有显著增强的抗肿瘤免疫反应。体外将非贴壁脾细胞暴露于CA4P不会增强其增殖。然而，用0.3μg/mL CA4P对贴壁脾细胞进行3小时预处理可显著增强混合的非贴壁脾细胞的增殖和γ干扰素产生，部分原因是一氧化氮减少。将一氧化氮合酶抑制剂N-硝基-L-精氨酸甲酯与CA4P和免疫治疗相结合可进一步延缓肿瘤生长。
与单独的任何一种治疗相比，对肿瘤逐渐生长的大鼠同时进行免疫治疗和低剂量CA4P治疗可显著增强治疗效果，并导致抗肿瘤免疫反应增强。
